The experimental literature regarding the conformational effects of threonine (Thr) phosphorylation in intrinsically disordered proteins/regions presents an apparent paradox. In some contexts, Thr phosphorylation appears to stabilize beta conformations, while in others – including a proline-rich region of the tau protein – it appears to stabilize PPII conformations. In this work we present MD simulations of several small peptide systems that suggest that the identity of the residue immediately C-terminal to the Thr phosphorylation site is the primary determinant of how the conformational ensembles of these peptides change upon phosphorylation. These data help resolve the aforementioned paradox by demonstrating that the existence of a proline residue in this position prevents the formation of a phosphate-to-backbone hydrogen bond that would otherwise stabilize beta conformations. This in turn has implications for the role of phosphorylation in proline-rich motifs, which are both often disordered and recognition sites for protein-protein interactions. Finally, our simulations provide specific, testable hypotheses that can be confirmed – or falsified – with appropriate NMR experiments.

Conformational effects of threonine phosphorylation in proline-rich disordered motifs

254th National Meeting (2017)

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